Ocular ultrasound probe

ABSTRACT

Devices, systems and methods for ocular ultrasound are provided having therapeutic and/or diagnostic applications. In one aspect, an ocular probe is disclosed that is uniquely configured for use in the eye on the basis of shape and frequency. The ocular probe may be multi-functional, providing sensor, optical or other functionality in additional to ultrasound energy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/488,505 filed May 20, 2011, titled “Ocular Ultrasound Probe” and U.S.Provisional Application No. 61/577,525, filed Dec. 19, 2011, titled“Ocular Ultrasound Probe,” both of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to devices, systems and methods for ocularultrasound having therapeutic and/or diagnostic applications.

BACKGROUND OF THE INVENTION

Proper functioning of the eye requires nourishment from the vascularsystem. A disruption in blood flow can lead to a disruption in vision oreven blindness. A variety of diseases and disorders can cause disruptionin ocular blood flow.

Retinal vein occlusion (RVO) is a condition in which a blood clot slowsor stops circulation in a vein within the retinal tissue. There are twoprimary types of RVO. Central retinal vein occlusion (CRVO) involves ablockage of the main vein of the retina. Branch retinal vein occlusion(BRVO) involves a blockage of the tributary vein(s) of the retina. RVOis the second most common retinal vascular disease and is a significantcause of blindness worldwide. In the U.S. alone, 150,000 new cases ofRVO occur each year.

Various pharmacological and non-pharmacological treatments for RVO havebeen explored. Pharmacological treatments include systemic/intravitrealthrombolytics, intravitreal triamcinolone (SCORE: Standard Care Vs.Corticosteroid for Retinal Vein Occlusion; Ozurdex, Allergan), andintravitreal anti-VEGF (bevacizumab, ranibizumab, pegaptanib).Non-pharmacological treatments for BRVO include limited sheathmanipulation, macular laser and sheathotomy. Non-pharmacologicaltreatments for CRVO include laser/surgical chorioretinal anastomosis,posterior scleral ring sheathotomy, radial optic neurotomy and retinalvein cannulation. The surgical approaches to RVO treatment aretechnically challenging, but when successful, produce significantresults.

U.S. Patent Application Publication No. 2009/0030323 to Fawzi et al.,titled “Ultrasound and Microbubbles in Ocular Diagnostics and Therapies”described methods, systems, and techniques for applyingcontrast-enhanced ultrasound to locate areas of blockage within retinalvessels and to break up clots that are causing damage.

There remains a need for improved treatments for diseases and disorderscaused by disruption in ocular blood flow, including RVO.

SUMMARY OF THE INVENTION

Disclosed herein are devices, systems and methods for ocular ultrasoundhaving therapeutic and/or diagnostic applications. In one aspect, thepresent invention is an ocular ultrasound probe which may be configuredfor extraocular or intraocular use as described herein.

In a first embodiment, the present invention is an ocular ultrasoundprobe comprising a housing and a transducer element contained within thehousing, wherein the transducer element provides a source of ultrasoundat a frequency of less than about 10 MHz. In a particular embodiment,the ultrasound frequency is less than about 5 MHz.

In a second embodiment, the present invention is an ocular ultrasoundprobe comprising a housing and a transducer element contained within thehousing, wherein the ocular ultrasound probe is configured to permitsimultaneous application of ultrasound energy and viewing of the site towhich the ultrasound energy is applied.

In a third embodiment, the present invention is an ocular ultrasoundprobe that is self-retaining or primarily self-retaining during use,i.e., application of ultrasound energy. In a particular embodiment, theself-retaining ocular ultrasound probe further comprises a securingmeans. In a specific embodiment, the securing means is an adhesive orstrap.

In a fourth embodiment, the present invention is an ocular ultrasoundprobe configured to permit application of ultrasound energy to the eyewhile advantageously limiting ultrasound energy delivery to thecrystalline lens.

The configuration of the ocular ultrasound probe may vary according toconditions of use. In one embodiment, the present invention is an ocularultrasound probe comprising a housing or probe head in the shape of adisc, a half-circle, a crescent, a wedge or a ring. In a particularembodiment, the ocular probe is configured for use with an ultrasoundbath.

The ocular ultrasound probe may optionally further comprise a sensor topermit the user to determine if the probe is in contact with thepatient's eye. The sensor may be any suitable sensor known for use withdetermining contact with another surface. In one embodiment, the sensormay sense or measure pressure or resistance at the point of contact withthe patient. In a particular embodiment, the sensor means is amechanical or electrical spring.

The ocular ultrasound probe of the present invention may optionallyfurther comprise an optical component. In one embodiment, the opticalcomponent is an imaging component. In another embodiment, the opticalcomponent is a laser.

The ocular ultrasound probe may optionally further comprise an RFIDcomponent, e.g., an RFID tag or reader.

In a fifth aspect, the present invention is a system for deliveringultrasound energy to the eye, which system includes an ocular ultrasoundprobe and a processor.

In a sixth aspect, the present invention is a method of treating adisease or disorder of ocular blood flow comprising supplyingmicrobubbles to a blockage within a retinal vessel and applyingultrasound energy to the eye using the ocular ultrasound probe of thepresent invention in order to reduce or eliminate the blockage.

In one embodiment, the disease or disorder is retinal vein occlusion.

Optionally, the method further comprises viewing the blockage prior to,during or after the application or microbubbles or ultrasound energy.

Optionally, the method further comprises administering one or moreadditional treatments to the eye.

BRIEF DESCRIPTION OF THE DRAWINGS

Aspects of the disclosure may be more fully understood from thefollowing description when read together with the accompanying drawings,which are to be regarded as illustrative in nature, not as limiting. Thedrawings are not necessarily to scale, emphasis instead being placed onthe principles of the disclosure.

FIG. 1 shows the collapse of retinal veins and sclerosis.

FIG. 2 shows the cavitation of microbubbles using ultrasound to dislodgea thrombus. (Source: Cerevast Therapeutics, Inc.)

FIG. 3 shows an ultrasound image of microbubble flow in retinal vessels.

FIG. 4 shows images from a flourescein angiogram in rabbit showingnormal perfusion of the retinal vessels (top row), photothrombosis(middle row) and reperfusion after sonolysis treatment (bottom row).

FIG. 5 shows an angiography of a retinal vessel treated withmicrobubble-assisted ultrasound.

FIG. 6 shows an angiography of a retinal vessel treated withmicrobubble-assisted ultrasound.

FIG. 7 shows a Doppler image of retina.

FIG. 8 is a chart depicting the mean venous blood velocity.

FIG. 9 is a chart depicting the normalization of retinal oxygen aftertreatment with microbubble-assisted ultrasound.

FIG. 10 shows an optical coherence tomography image after treatment withmicrobubble-assisted ultrasound.

FIG. 11 shows an angiography of a retinal vessel treated withmicrobubble-assisted ultrasound.

FIG. 12A is an illustration of an exemplary disc-shaped extraocularultrasound probe (A) shown placed on a closed eyelid.

FIG. 12B is an illustration of an exemplary ocular ultrasound probe andspring sensor, according to certain exemplary embodiments.

FIG. 12C is an illustration of an exemplary ultrasound probe, bath, andhuman subject, according to certain exemplary embodiments.

While certain embodiments are depicted in the drawings, one skilled inthe art will appreciate that the embodiments depicted are illustrativeand that variation of those shown, as well as other embodimentsdescribed herein, may be envisioned and practiced within the scope ofthe present disclosure.

DETAILED DESCRIPTION

Disclosed herein are devices, systems and methods for ocular ultrasoundhaving therapeutic and diagnostic applications.

The Ultrasound Probe

An ultrasound probe configured for ocular use is provided herein. Theocular ultrasound may be an extraocular ultrasound probe or anintraocular ultrasound probe, in each instance comprising a housing anda transducer element contained within the housing.

The transducer element provides the ultrasound component of the probe.The transducer is typically a piezoelectric material or single crystalmaterial which converts electrical energy to ultrasonic energy andultrasonic energy to electrical energy. The piezoelectric material maybe a ceramic, a polymer or a composite material. In a specificembodiment, the transducer element is lead zirconate titanate (PZT).

Transducers for use in the ocular ultrasound probe of the presentinvention may vary in configuration, including shape, size and/ororientation within the probe housing. PZT transducers, in particular,are desirable based on their ability to be shaped. In one embodiment ofthe present invention, the shape of the transducer element varies withthe shape of the housing. The configuration of the transducer may alsovary based on the shape of the ultrasound probe and can be linear,horizontal or vertical.

The ocular probe may contain a single transducer element or multipletransducer elements. Where multiple transducers are utilized within asingle probe, the transducers may be spaced regularly or irregularlywithin the casing. In a particular embodiment, multiple transducers areconfigured in a linear array.

The thickness of the active element determines the frequency of thetransducer, i.e., the number of wave cycles completed in one second,which is typically expressed in Kilohertz (KHz) or Megahertz (MHz).Generally, thin materials have high frequencies while thick materialshave low frequencies. Low frequencies are associated with longerwavelengths and generally penetrate deeper in materials. In a particularembodiment, the ocular ultrasound probe of the present invention has aPZT transducer element with a thickness of less than about 20 μm, lessthan about 15 μm, less than about 10 μm or less than about 5 μm.

In one embodiment, the ocular ultrasound probe of the present inventiongenerates frequencies in the range of from about 1 to about 20 MHz. In aparticular embodiment, the ocular ultrasound probe generates frequenciesof from about 1 to about 10 MHz. In another particular embodiment, theocular ultrasound probe generates frequencies of less than about 9,about 8, about 7, about 6, about 5, about 4, about 3, about 2 or about 1MHZ. In a specific embodiment, the ocular ultrasound probe generates afrequency of less than about 5 MHz. In a particular embodiment, thefrequency is less than about 10 MHz and the mechanical index (MI) isbelow about 0.5.

The ultrasound may be applied generally in a focused or directed manner,where focus refers to the convergence of the mechanical waves on aspecific point. The intensity, duration and resonant frequency may bealtered according to the particular result desired, for example,diagnostic imaging versus therapeutic use.

The configuration of the ocular probe is dictated by the conditions ofuse, where configuration variously refers to the shape of the housing,the shape of the transducer, any additional components contained withinthe housing as well as their orientation, and the external connectivityof the housing to one or more additional components within an ultrasoundsystem.

The shape of the housing may vary. In an exemplary embodiment, thehousing has a generally elongated shape having a proximal end and adistal end. In this elongated embodiment, the transducer is generallydisposed at the distal end of the probe (i.e., closest to the patient'seye), referred to as a probe head. The probe head is configured todirect ultrasound energy from the transducer to a target location on thepatient's body, i.e., the eye. The head portion may be a disk or roundshape, a half-circle shape, a crescent shape, a triangle/wedge shape, ora ring/torus shape. A handle/grip portion may be located at the proximalend of the housing, structured to enable a user to grasp the casing andposition the ultrasound probe adjacent to the treatment site. Thehandle/grip portion can include electrical switches which changes theparameters for operating the probe including turning it on and off. Innon-wireless embodiments, a cord for transferring data and powertypically extends from the proximal end of the ultrasound probe.

In another embodiment, the ocular probe is not elongated but relativelyflat. The term flat or relatively flat is used to describe an ultrasoundprobe having a top surface, a bottom surface and a sidewall, wherein thebottom and top surfaces have a width greater than the height of thesidewalls. The bottom surface refers to the surface in closest proximityto the patient during application of ultrasound, i.e., from which theultrasound energy is transmitted upon generation by transducer elementcontained within the housing. According to this embodiment, the flat orrelatively flat probe housing may be in the shape of a disk or roundshape, a half-circle shape, a crescent shape, a triangle/wedge shape, ora ring/torus shape.

In a particular embodiment, the ocular probe is an extraocular probeconfigured for positioning on the external surface of the patient'sbody, for example on the eyebrow or closed eyelid of the patient to betreated. The probe may be elongated or flat. Where the probe iselongated, the probe head is configured for positioning on the externalbody surface. When the probe is flat, the housing itself is configuredfor positioning on the external surface. FIG. 12(A) shows a disc-shapedultrasound probe placed on a closed eyelid of a patient.

In another embodiment, the ultrasound probe is configured forintraocular use, i.e., for use within the eye. When the use is internalor intraocular, the shape of the ultrasound probe (or the bath used incombination with the probe, as applicable) may be dictated by theshape/contour of the eye surface or eye socket. When the probe housingis elongated, the shape of the probe head is dictated by the eye surfaceor socket. When the probe is flat or relatively flat, the shape of thehousing is dictated by the eye surface or socket. An exemplaryultrasound probe can have a semi-spherical shape similar to a contactlens. The exemplary ultrasound probe can cover a portion of the eyesurface and can be placed in the same/similar location as contact lenswould be placed. It is also contemplated that the ultrasound probe canbe moved along the eye surface to various locations. In anotherparticular embodiment, the ultrasound probe is configured for use in theeye socket. For example, the ultrasound probe can cover most or all ofthe eye surface. An exemplary ultrasound probe includes an outer ringthat fits snuggly to the patient's eyelids.

In one embodiment, the ocular ultrasound probe advantageously permit theuser to simultaneously apply ultrasound energy and view the same, i.e.,view the target site to which ultrasound energy is being directed. In anexemplary embodiment, the ultrasound probe is configured to permit theultrasound operator or user to view the eye during ultrasoundapplication or while the ultrasound probe is in position for ultrasoundapplication using an microscope or other viewing instrument. In aparticular embodiment, the ultrasound probe has a half circle, torus,crescent, or wedge shape that permits the user to look into thepatient's eye during the ultrasound treatment using a microscope orother viewing instrument.

In another embodiment, the ocular ultrasound probe advantageouslypermits ultrasound energy to be delivered to the eye while limitingultrasound energy delivery to the crystalline lens. That is, the shapeof the probe is such that ultrasound energy can be delivered to thetarget site within the eye while avoiding the crystalline lens. Forexample, the torus shaped probe can be placed in the patient's eye suchthat the open center portion of the torus encircles the natural lens ofthe patient's eye, thereby preventing exposure to ultrasound energy.

According to one aspect of the invention, the ocular ultrasound probe isself-retaining or primarily self-retaining, where self-retaining refersto the ability to remain fixed in position at the site of use whileultrasound is applied without the need for the user to hold the probe inplace, either at all or for extended periods of time otherwise required.This self-retaining probe can be extraocular or intraocular, where theunaided or relatively unaided retention is possible due to theconfiguration of the housing and/or the use of one or more securingmeans.

In one embodiment, the ultrasound probe is advantageously configured tolimit or obviate the need for the user or operator to hold theultrasound probe as the method is performed. The need to hold the probeduring use is either completely eliminated or reduced to some degreeover the duration required by a standard probe (e.g., less than about 60minutes, about 45 minutes, about 30 minutes, about 15 minutes, about 10minutes or about 5 minutes). For example, an exemplary ultrasound probecan be positioned proximate a target, i.e., the patient's eye, usingsecuring means or attachment device. For example, the attachment devicemay retain the ultrasound probe such that neither the user nor thepatient are required to position or hold the ultrasound probe in placeduring application. In a particular embodiment, the securing means is anadhesive applied to the surface of the probe and/or the patient. Theadhesive may be, for example, a single or multiple layer adhesive. Theadhesive may be capable of single use/attachment or it may bere-sealable upon relocation of the ultrasound probe. In an alternateembodiment, the attachment device can include an apparatus or deviceworn by the patient to secure the ultrasound probe in place physicallyagainst the target location. An exemplary attachment device can includea strap or headpiece for securing the ultrasound probe in place at thepatient's eye. For example, the attachment device can be configuredsimilar to an eye patch (‘pirate patch”) attached around the patient'shead by an elastic or cloth band, or as an adhesive bandage.

Exemplary self-retaining ultrasound probes can be a donut shape, a discshape, a half-circle shape, a crescent shape, a wedge shape or aring/torus shape.

In one embodiment, the present invention is a self-retaining extraocularprobe where the ability to self-retain is provided by the configurationor shape of the probe housing or the probe further comprises one or moresecuring means. The securing means may be any suitable means includingbut not limited to an adhesive (to be applied to the probe or thepatient or both) or a strap. In a particular embodiment, the extraocularprobe is flat and fits within a pirate patch-type securing means whichpositions the probe on the eyebrow or closed eyelid of the patient whenworn by the patient.

In an exemplary embodiment, the self-retaining ultrasound probe is anintraocular probe that may be contoured, similar to the cornea, to siton the surface of the patient's eye and fit in or adjacent to thepatient's eyelids. An exemplary self-retaining intraocular ultrasoundprobe can have a semi-spherical shape similar to a contact lens. Theexemplary ultrasound probe can cover a portion of the eye surface andcan be placed in the same/similar location as contact lens would beplaced. It is also contemplated that the ultrasound probe can be movedalong the eye surface to various locations. In another particularembodiment, the ultrasound probe is configured for use in the eyesocket. For example, the ultrasound probe can cover most or all of theeye surface. An exemplary ultrasound probe includes an outer ring thatfits snuggly to the patient's eyelids. In one embodiment, theself-retaining intraocular ultrasound probe would be operational whenthe patient's eyelid is closed.

The ultrasound probe may be used alone or in combination with a bath,such as a water bath or gel bath. The ultrasound probe may be attachedto the bath or rest within the bath, and in either case, may beconfigured particularly for this method. Use of the bath permits thesonographer to focus the ultrasound on the front of the patient's eye.For example, in a particular embodiment when the ultrasound probe isfunctioning at a low frequency, such as 1 MHz, it may be difficult tofocus on the physical structures in the front of the patient's eye,e.g., the trabecular meshwork (tissue in the eye located around the baseof the cornea providing fluid drain for the eye). By using a bath, thedistance between the ultrasound probe and the target tissue/structure isincreased, thereby permitting focusing of the ultrasound at the targettissue/structure. In a particular embodiment, an exemplary ultrasoundprobe can be used in conjunction with a bath for anterior ocularstructures. In a particular embodiment, an exemplary ultrasound probecan be used in conjunction with a bath for the treatment of glaucoma. Anexemplary bath can be configured to be placed in the eye socket similarto a contact lens. Another exemplary embodiment, illustrated in FIG. 12Cshows an ultrasound probe (D) can be attached to the bath (E), which isthen placed in contact with the eye (F). The ultrasound probe may beattached to the bath (e.g., by pre-fabrication) or simply rest withinit.

In an exemplary embodiment, the ultrasound probe can include both anultrasound component (e.g., transducer) and an optical component. Theoptical component can be an imaging component or a treatment component.The optical component can include, for example, a light source. Thislight source may be any known to one of skill in the art, including, butnot limited to light optical fibers, light emitting diodes (LED), xenonarc lamps, halogen bulbs, lasers and the like. In a particularembodiment, the ultrasound probe has a built-in light optical fiber foremitting light onto the patient's body. In one embodiment, the lightsource emits energy with wavelengths in the visible light spectrum. Inother embodiments, the light source emits energy with wavelengthsoutside the visible light spectrum. An exemplary ultrasound probe mayhave separate compartments or housings for the transducer and opticalcomponents. In an alternative embodiment, the transducer and the opticalcomponents are housed in a single unit. In one embodiment, theultrasound probe is designed to allow simultaneous visualization ofhuman body parts during ultrasound application. In one embodiment, theultrasound probe combines ultrasound and optical viewing to allow theultrasound to be used with a microscope and/or digital viewing system.In one embodiment, the ultrasound is configured for use in opticalcoherence tomography (OCT).

In an exemplary embodiment, the ultrasound probe is configured for usein non-ocular applications. For example, the probe may be used on otherregions of the body where ultrasound or ultrasound and imagingcapabilities are desired. In a particular embodiment, as describedfurther herein, the ultrasound probe provides ultrasound energy todiagnose the presence of a blood clot or blockage. In a particularembodiment, as described further herein, the ultrasound probe providesultrasound energy to activate or create inertial or unstable cavitationin a microbubble contrast agent. In another particular embodiment, theultrasound probe provides ultrasound energy to activate or createinertial or unstable cavitation in a microbubble contrast agent andoptical viewing to permit simultaneous viewing of the effects ofsonolysis on retinal blood flow and retinal structures. In one example,ocular blood flow may be monitored and adverse effects, such asbleeding, may be identified using the ultrasound probe described herein.In another particular embodiment, the ultrasound probe providesultrasound and optical viewing to create inertial or unstable cavitationin a microbubble contrast agent and simultaneous viewing of the effectsof sonolysis on phacomemulsification (ultrasound assisted breaking ofthe crystalline lens). In another particular embodiment, the ultrasoundprobe provides ultrasound energy to permit activation or create inertialor unstable cavitation of a contrast agent or microbubble containingdrug or dye label. In another particular embodiment, the ultrasoundprobe provides ultrasound energy to permit activation or create inertialor unstable cavitation of a contrast agent or microbubble containingdrug or dye label as well as optical viewing to permit, and simultaneousviewing of, the effects of sonolysis on drug and/or dye release in theeye. In another particular embodiment, the ultrasound probe providesultrasound (and optionally, optical viewing) to create inertial orunstable cavitation in a microbubble contrast/dye agent (for example,protoporphyrin) and, optionally simultaneous application of laser toexcite the dye). In one embodiment, the ultrasound probe allows accuratemeasurement of intraocular lens calculations and the accuratemeasurement of intraocular structures such as the retina as well aspathological structures such as tumors. In one particular embodiment,the optical measure is interferometry. In one embodiment, the ultrasoundprobe combines ultrasound and optical measures such as lasers to allowcombining ultrasound diagnostics and therapeutics with laser diagnosticsand therapeutics.

According to one exemplary embodiment, the present ultrasound probe hasa tip/cover surface that is detachable, disposable, and/or sterilizable.The tip/cover surface may be pre-packaged. In one embodiment, theultrasound probe and/or the detachable tip/covers surface are packagedwith tools to attach the tip/cover to the ultrasound probe.

In one embodiment, the ultrasound probe includes a sensor to permit theultrasound machine or user to determine if the probe is in contact withthe eye, for example the eyelid or the eye surface. The sensor may beany suitable sensor, including but not limited to, a device to sense ormeasure pressure or resistance at probe when in contact with thepatient. In a particular embodiment, the sensor includes a mechanical orelectrical spring to measure pressure or resistance at the point ofcontact with the patent. An exemplary sensor includes the mechanical orelectrical spring located around the perimeter of the housing at theportion of the ultrasound probe including the transducer. In anexemplary embodiment, the sensor includes a mechanical or electricalspring located within the attachment device. In one embodiment, thespring is a ring-shaped spring that is compressed and eithermechanically or electrically confirms contact with the eye, e.g., theeyelid or the eye surface. An exemplary sensor is illustrated in FIG.12(B) including the ultrasound probe (B) and the spring (C). In analternate embodiment, the ultrasound probe can include capacitancesensors such that the ultrasound probe or attachment device includessensors for detecting a change in the electrical field at the surface ofthe probe or attachment device caused by contact with the patient.

In one embodiment, the device is an ultrasound probe wherein suchultrasound probe is either free standing or connected to additionalcomponents to provide an ultrasound system. The additional componentsmay include, for example, an amplifier, a processor, a display device,and a keyboard and/or other input and output devices. In one embodiment,the ultrasound probe is wirelessly connected to an additional component.In a particular embodiment, the ultrasound probe includes a Bluetoothmodule or other suitable short-range wireless device for wirelesscommunication to the ultrasound machine for power and data.

In another embodiment, the present invention is a system for deliveringultrasound energy to the eye, which system includes an ultrasound probeand a processor. Additional components may include a transducercontroller for altering the frequency, amplitude or duration of thepulse emitted from the ultrasound probe), a display, an input function(e.g., a keyboard), an information storage device and/or a printer.

The system or any component of the system, including the ultrasoundprobe, may optionally use radio frequency identification (RFID)technology. In a specific embodiment, the ultrasound probe may have anRFID reader that can read an RFID tag present, for example, on anultrasound machine or a vial of medicine. In another embodiment, theultrasound probe may have an RFID tag and an RFID reader may be presentin another component of the ultrasound system, remote from theultrasound reader. In a particular embodiment, the ultrasound probe isactivated when the RFID or other similar marking on the transducerand/or housing is recognized by an ultrasound machine or when the RFIDof the transducer and/or housing plus the RFID on any associated othercomponent used with the ultrasound probe (e.g., drug vial, ultrasoundgel) are both recognized by the ultrasound machine.

Methods of Use

The devices and systems of the present invention can be used in avariety of therapeutic and diagnostic applications, as would beunderstood to one of skill in the art. In certain embodiments, thedevice and method provide dual functionality where that is desired fortherapeutic and/or diagnostic applications.

In an exemplary embodiment, the present invention is a method ofdiagnosing an ocular disease or disorder, such as retinal vein occlusionby applying ultrasound energy to the eye using the ocular ultrasoundprobe or system disclosed herein.

In another embodiment, the present invention is a method of treating anocular disease or disorder, such as retinal vein occlusion, using theocular ultrasound probe of the present invention. In a particularembodiment, the method involves administering a therapeuticallyeffective amount of a microbubble contrast agent to the patient andapplying ultrasound energy to the eye using the ultrasound probe orsystem disclosed herein, wherein the ultrasound energy is applied at afrequency of less than about 10 MHz or less than about 5 MHz. In aspecific embodiment, the ultrasound energy is applied at about 10, about9, about 8, about 7, about 6, about 5, about 4, about 3, about 2 orabout 1 MHz with a mechanical index (MI) of about 0.5.

In a particular embodiment, the ultrasound probe can be used to activateor create inertial or unstable cavitation in a microbubble contrastagent and, optionally, to allow simultaneous viewing of the effects ofsuch sonolysis on retinal blood flow and retinal structures. In oneexample, ocular blood flow may be monitored and adverse effects, such asbleeding, may be identified using the methods described herein.

Microbubbles are tiny, gas-filled lipid, or fat, bubbles that can beinjected into the bloodstream, where they remain inactive unlessstimulated. Ultrasound energy or waves directed at microbubbles causethe microbubbles to vibrate and return a unique echo within thebloodstream that produces a dramatic distinction, or high “contrast,”between blood vessels and surrounding tissue, thus enabling cliniciansto visualize areas of restricted blood flow. Specialized Dopplerultrasound, which measures the rate and volume of blood flow, canfurther pinpoint the extent and severity of blockage caused by bloodclots. In one embodiment, visualization is further enhanced utilizingthe optical aspects of the probe. In a particular embodiment, the methodutilizes microbubbles having from about 1 to about 10 microns indiameter.

Contrast-enhanced ultrasound, further enhanced with the addition ofoptic visualization, not only allows one to locate areas of blockagewithin retinal vessels, but also can be used to break up clots that arecausing damage. In some instances, the vibration effect of theultrasound itself may suffice to dislodge clots. In other instances, themicrobubbles are ruptured by the sonic energy and the clot ismechanically disrupted. In addition to identifying and treating thedamaged area, the ultrasound produces an initial image that may serve asa baseline for monitoring the effect of treatment on the vessel. Thisinitial image may be further enhanced with the use of the opticalaspects of the probe.

In one embodiment, the present invention is a method of treating anocular disease or disorder, such as retinal vein occlusion, in a patientin need thereof, by administering a therapeutically effective amount ofa microbubble contrast agent to the patient and applying ultrasoundenergy to the eye using the ultrasound probe or ultrasound disclosedherein. The microbubbles may be administered to the patient by anysuitable method, including, for example, intravenous injection,intraocular injection or extraocular administration. In a particularembodiment, the microbubbles are delivered by intravenous injection intothe systemic circulation. In another particular embodiment, themicrobubbles are delivered into the retinal blood vessels by way of acatheter. In another particular embodiment, the microbubbles aredelivered by intraocular injection. In a still further embodiment, themicrobubbles are administered to the patient by placing a drop of fluidor liquid containing the gas microbubbles suspension on the surface ofthe eye.

The ultrasound energy can be applied generally or in a focused ordirected manner. The intensity, duration and resonant frequency may bealtered according to the particular result desired, for example,diagnostic imaging versus therapeutic use. In a particular embodiment,the frequency is from about 1 to about 10 MHz and the mechanical indexis below about 0.5. In a specific embodiment, the frequency is fromabout 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2or about 1 MHz. In a specific embodiment, the frequency is less thanabout 5 MHz.

After a period ranging from a few minutes to a few hours the eye isinspected using a microscope and then if need be, treatment is continuedor discontinued if it has met its end goal. The end goal of thetreatment can be establishing reflow in an occluded vessel, or breakingup a lens or lowering intraocular pressure (IOP). At the end of theprocedure the ultrasound probe is removed as well as the intravenousinjection line.

Optionally, the method of treatment involves viewing the treatment area.The treatment area may be viewed prior to treatment, during treatment(i.e., simultaneously with application of ultrasound energy or othertreatments) or after treatment. Viewing the treatment area prior to orduring treatment may permit the user to direct the treatment in anoptimal manner, while post-treatment viewing may permit the user todetermine the effectiveness of the treatment.

In one embodiment, the method involves simultaneous visualization orimaging of human body parts. For example, the user may visualize thepatient's body parts using ultrasound images while simultaneouslyvisualizing portions of the patient's body using the disclosed opticalelement.

In one embodiment, the ultrasound probe is centered on the body partduring surgery or clinical examination (e.g., torus/ring-shaped probe orcontact lens-shaped probe placed on the eye during surgery or clinicalexaminations).

Optionally, the method of treatment involves one or more additionaltherapeutic steps. In a particular embodiment, the method also involvesapplying laser energy to the eye using the ultrasound probe or systemdisclosed herein. In a particular embodiment, the method involvesapplying laser energy to the eye to provide one or more of photoacoustics, photo excitation or photocoagulation.

In one embodiment, the method combines diagnosis and treatment. In aparticular embodiment, the present invention is a method of diagnosingan ocular disease or disorder, such as retinal vein occlusion, in apatient in need thereof, by applying ultrasound energy to the eye usingthe ultrasound probe or system disclosed herein in order to identify anarea of blockage within the vessels of the eye.

In one embodiment, the ultrasound probe can be used to accuratelymeasure intraocular lens calculations and to accurately measureintraocular structures such as the retina as well as pathologicalstructures such as tumors.

In a particular embodiment, the ultrasound probe can be used to activateor create inertial or unstable cavitation in a microbubble contrastagent and, optionally, to allow simultaneous viewing of the effects ofsuch sonolysis on retinal blood flow and retinal structures. In oneexample, ocular blood flow may be monitored and adverse effects, such asbleeding, may be identified using the methods described herein.

In a particular embodiment, the ultrasound probe can be used to activatethe microbubbles (which may be located within the eye, including withinthe vasculature of the eye or within the eye tissue including the lensmaterial or trabecular meshwork) in order to create inertial or unstablecavitation in a microbubble containing drug or dye label and optionally,allow simultaneous viewing of the effects of such sonolysis on drugand/or dye release in the eye. In one embodiment, the microbubbles maybe coated or filled with a therapeutic agent, for example, a drug, withultrasonic shock waves activating the coating or causing mini explosionsto release the therapeutic. Loading the microbubbles with a therapeuticagent, visualizing their presence at the diseased site using theultrasound and optical diagnostic mode, and then activating themicrobubbles to release their contents at the targeted lesion/region canbe a powerful and effective way to reverse occlusion without harmingother areas of the eye or body.

In another particular embodiment, the ultrasound probe can be used tocreate inertial or unstable cavitation in a microbubble contrast agentand optionally, allow simultaneous viewing of the effects of suchsonolysis on phacomemulsification (ultrasound assisted breaking of humancrystalline lens).

In another particular embodiment, the ultrasound probe can be used tocreate inertial or unstable cavitation in a microbubble contrast/dyeagent (for example, protoporphyrin) and optionally, allow simultaneousapplication of laser to excite the dye.

The exemplary methods and acts described in the embodiments presentedpreviously are illustrative, and, in alternative embodiments, certainacts can be performed in a different order, in parallel with oneanother, omitted entirely, and/or combined between different exemplaryembodiments, and/or certain additional acts can be performed, withoutdeparting from the scope and spirit of the invention. Accordingly, suchalternative embodiments are included in the inventions described herein.

Although specific embodiments have been described above in detail, thedescription is merely for purposes of illustration. It should beappreciated, therefore, that many aspects described above are notintended as required or essential elements unless explicitly statedotherwise. Modifications of, and equivalent acts corresponding to, thedisclosed aspects of the exemplary embodiments, in addition to thosedescribed above, can be made by a person of ordinary skill in the art,having the benefit of the present disclosure, without departing from thespirit and scope of the invention defined in the following claims, thescope of which is to be accorded the broadest interpretation so as toencompass such modifications and equivalent structures.

What is claimed is:
 1. A method for treating a disease or disorder of anocular blood flow, the method comprising: a) supplying microbubbles to ablockage within a retinal vessel, said supplying including supplying themicrobubbles to an occluded retinal vein, b) using an ocular ultrasoundprobe, which includes a housing and an ultrasound transducer element inthe housing, wherein an outer surface of said housing has a shape of asemicircle, a crescent, or a wedge and is dimensioned to be placed incontact with and onto an eye or an eyelid at a first locationcorresponding to a second location, the second location being a locationdesignated for placement of a contact lens on the eye, to position saidprobe at said first location such that the outer surface is in contactwith a surface of the eye or the eyelid; and to retain and secure theprobe at the eyelid with a use of an outer ring of the housing to holdthe probe in place, and c) reducing or eliminating the blockage byapplying ultrasound energy having a frequency in a range between 1 MHzand 10 MHz from the so-secured probe to a retinal site in the eye toinitiate cavitation at the microbubbles while avoiding delivery of saidenergy to a crystalline lens of the eye and simultaneously opticallyviewing the retinal site with an optical viewing instrument through anopening in the ultrasound transducer.
 2. The method of claim 1, whereinthe supplying the microbubbles to the blockage comprises supplying themicrobubbles having a diameter in a range from 1 micron to 10 microns.3. The method of claim 1, wherein said using the ocular ultrasound probeincludes using said probe that further includes said optical imagingcomponent in said housing.
 4. The method of claim 1, further comprisingestablishing contact between said probe and a surface of the eye.
 5. Themethod of claim 4, further comprising moving said probe along thesurface of the eye.
 6. The method of claim 3, further comprisingadministering one or more additional treatments to the eye.
 7. Themethod of claim 1, wherein said supplying the microbubbles to theblockage within the retinal vessel comprises supplying the microbubblesthat include a therapeutic agent on surfaces or within interiors of themicrobubbles.
 8. The method of claim 7, wherein said applying theultrasound energy to the eye comprises rupturing the microbubbles torelease the therapeutic agent.
 9. The method of claim 1, wherein saidsupplying the microbubbles to the blockage within the retinal vesselcomprises supplying a microbubble contrast agent to the blockage. 10.The method of claim 1, further comprising optically exciting a dye agentin said microbubbles that have been supplied to the blockage.
 11. Themethod of claim 6, wherein the administering said one or more additionaltreatments to the eye comprises photocoagulating ocular tissues using alaser or applying photoacoustic energy to the eye using the laser. 12.The method of claim 1, wherein said using the ocular ultrasound probeincludes using the probe that includes an ultrasound bath juxtaposedwith the transducer element such that, during said using, the ultrasonicenergy is applied to the target site through the ultrasound bath. 13.The method of claim 1, further comprising viewing the blockage throughan opening in the ultrasound transducer.
 14. The method of claim 1,wherein said optically viewing includes viewing the blockage prior to orafter said supplying the microbubbles to the blockage.
 15. The method ofclaim 1, wherein said optically viewing includes viewing the blockageprior to or after said applying the ultrasound energy to the eye.